A consequence of immature breathing induces persistent changes in hippocampal synaptic plasticity and behavior: a role of prooxidant state and NMDA receptor imbalance

Area of Science:

• Neuroscience
• Developmental Biology
• Perinatal Medicine

Background:

• Premature birth can lead to underdeveloped breathing, causing neonatal intermittent hypoxia (nIH).
• nIH is associated with an increased risk of later-life neurocognitive deficits.
• The precise mechanisms underlying nIH-induced neurophysiological changes are not fully understood.

Purpose of the Study:

• To investigate the impact of nIH on hippocampal synaptic plasticity and NMDA receptor (NMDAr) expression in neonatal mice.
• To explore the role of the prooxidant state in nIH-induced neurophysiological and behavioral deficits.
• To evaluate the therapeutic potential of antioxidant treatment during a critical window.

Main Methods:

• Neonatal mice were exposed to intermittent hypoxia (nIH).
• Hippocampal synaptic plasticity and NMDAr subunit expression (GluN2A, GluN2B) were assessed.
• Mice were treated with the antioxidant manganese (III) tetrakis (1-methyl-4-pyridyl)porphyrin (MnTMPyP) either during or after nIH exposure.

Main Results:

• nIH induced a prooxidant state, leading to impaired synaptic plasticity and altered NMDAr subunit composition (increased GluN2B/GluN2A ratio).
• These deficits persisted into adulthood, accompanied by spatial memory impairments.
• Antioxidant treatment during nIH mitigated both immediate and long-term effects, but post-nIH treatment was ineffective.

Conclusions:

• The prooxidant state plays a critical role in nIH-induced neurophysiological and behavioral deficits.
• Targeting the prooxidant state during a specific therapeutic window early in life may prevent long-term neurocognitive consequences of unstable breathing.
• Early intervention is key for mitigating the lasting effects of neonatal intermittent hypoxia.